CC Homozygosity Research Articles

Association of hyaluronan and proteoglycan link protein 1 gene with the need of home oxygen therapy in premature Japanese infants with bronchopulmonary dysplasia

Background Bronchopulmonary dysplasia (BPD) has a lasting effect on the respiratory function of infants, imposing chronic health burdens. BPD is influenced by various prenatal, postnatal, and genetic factors. This study explored the connection between BPD and home oxygen therapy (HOT), and then we examined the association between HOT and a specific single-nucleotide polymorphism (SNP) in the hyaluronan and proteoglycan link protein 1 (HAPLN1) gene among premature Japanese infants. Materials and methods Prenatal and postnatal data from 212 premature infants were collected and analyzed by four SNPs (rs975563, rs10942332, rs179851, and rs4703570) around HAPLN1 using the TaqMan polymerase chain reaction method. The clinical characteristics and genotype frequencies of HAPLN1 were assessed and compared between HOT and non-HOT groups. Results Individuals with AA/AC genotypes in the rs4703570 SNP exhibited significantly higher HOT rates at discharge than those with CC homozygotes (odds ratio, 1.20, 95% confidence interval, 1.07–1.35, p = .038). A logistic regression analysis determined that CC homozygotes in the rs4703570 SNP did not show a statistically significant independent association with HOT at discharge. Conclusions Although our study did not reveal a correlation between HAPLN1 and the onset of BPD, we observed that individuals with CC homozygosity at the rs4703570 SNP exhibit a reduced risk of HOT.

Polymorphic Variants in the Vitamin D Receptor and Clinical Parameters of Rheumatoid Arthritis Patients Undergoing Anti-TNF Treatment.

Vitamin D levels have been related to the severity and progression of various autoimmune disorders. In this study, we aimed to investigate the impact of genetic variability in the vitamin D receptor (VDR) gene on disease susceptibility and progression in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor (TNF) inhibitors. The study comprises 121 RA patients subjected to anti-TNF therapy genotyped for four VDR polymorphic variants: rs1544410 (BsmI), rs2228570 (FokI), rs731236 (TaqI), and rs7975232 (ApaI). There was no significant association between RA susceptibility and VDR genetic variants. The study results revealed that patients with the rs2228570 CC genotype were characterized by lower vitamin D3 levels (p = 0.028) than those with the T allele. Also, the vitamin D3 levels (p = 0.029) and age at diagnosis (p = 0.017) were significantly lower in rs7975232 A allele carriers compared to CC homozygotes. However, after 6 months of therapy, the A allele seemed to be related to lower disease activity score 28 (DAS28) values (p = 0.030) and more common in patients who achieved remission (p = 0.004) compared to the CC genotype. Concerning other investigated polymorphisms, patients carrying rs1544410 AA and rs731236 CC homozygosity had lower C-reactive protein (CRP) levels before therapy (p = 0.009). In conclusion, VDR rs2228570 and rs7975232 polymorphic variants were found to be related to vitamin D3 levels. Moreover, the genotyping of rs7975232 was also useful in evaluating disease onset and disease activity after 6 months of therapy with TNF inhibitors in RA patients.

Evaluation of metabolic disorders and aging rates depending on SIRT1 polymorphism in patients with arterial hypertension and subclinical hypothyroidism

There is an increase in the frequency and severity of metabolic disorders in patients with arterial hypertension (AH) in combination with subclinical hypothyroidism (SH), that is accompanied by accelerated aging rates, but the research findings on the aging rates in this category of patients are extremely few in number. Therefore, the aim of our study was to assess metabolic disorders and the aging rates depending on the SIRT1 rs7069102 polymorphism in patients with AH and SH. A total of 132 patients with a median age of 47.6 years were included in the study and divided into 3 groups: a control group (n=30), a group of patients with AH without SH (n=49) and patients with AH in combination with SH (n=53). Anthropometric parameters, biochemical parameters, pro-inflammatory and oxidative states were evaluated in all pa­tients. The aging rates were assessed using two different methods. The frequencies of SIRT1 rs7069102 genotypes carriers in the study sample of patients were 8% for the CC genotype, 51% for the CG genotype and 41% for the GG genotype. There was a significant difference in the incidence of CC homozygosity and carriers of the G allele between groups of patients with AH depending on the SH presence (p<0.001). We showed that carriers of the G allele and GG genotype of the SIRT1 gene (rs7069102) polymorphic marker with AH and SH had significantly higher (p<0.05) insulin resistance, higher levels of low-density lipoprotein cholesterol, alkaline phosphatase, C-reactive protein and lower glomerular filtration rate, which negatively affected the aging processes in this category of patients. In addition, patients with AH had a marked effect of carrying the G allele on the lipid profile and biological age of patients. Therefore, timely detection of a polymorphic variant of the SIRT1 gene may be effective in premature aging prevention in patients with AH and SH.

Study of common hypertriglyceridaemia genetic variants and subclinical atherosclerosis in a group of women with SLE and a control group

ObjectiveSLE is associated with increased cardiovascular risk (CVR). High serum concentrations of triglyceride-rich lipoproteins and apolipoprotein B-rich particles constitute the characteristic dyslipidaemia of SLE.MethodsA cross-sectional study was conducted to study...

The Genetic Variants of NOTCH3 (6746T>C) and PSMA6 (-8C>G) as Possible Risk Factors of Psoriasis Development.

Advances in genotypic technologies enable identification of possible associations between genetic variants of certain genes and increased risk of developing plaque psoriasis or psoriatic arthritis. The aim of the study was to analyze the NOTCH3 (6746T>C) (rs1044009) and PSMA6 (-8C>G) (rs1048990) polymorphisms and their role in genetic susceptibility to psoriasis. The study included 158 psoriatic patients and 100 healthy controls. The frequencies of the NOTCH3 genotypes differed between the psoriatic patients and healthy controls (p = 0.050). No differences were found in the distribution of PSMA6 genotypes and alleles between the psoriatic patients and healthy controls. The studied psoriatic patients presented a higher frequency of the CC genotype of PSMA6 compared to the healthy controls (8.8% vs. 2%, respectively). Psoriatic arthritis was more frequent among patients with the CC genotype of PSMA6 (p = 0.059). CC homozygosity of NOTCH3 was more commonly observed in the studied psoriatic patients than in the healthy controls (OR = 4.76, p = 0.032). The obtained data suggest that genetic variants of NOTCH3 (6746T>C) and PSMA6 (-8C>G) genes may play significant roles in psoriatic patients. Further studies are necessary to unequivocally determine their role as genetic risk factors of psoriasis development.

Asymptomatic Carotid Atherosclerosis Cardiovascular Risk Factors and Common Hypertriglyceridemia Genetic Variants in Patients with Systemic Erythematosus Lupus.

SLE is associated with increased cardiovascular risk. The objective of this study was to determine the prevalence of asymptomatic carotid atherosclerosis to analyze its relationship with dyslipidemia and related genetic factors in a population of patients with SLE. Seventy-one SLE female patients were recruited. Carotid ultrasound, laboratory profiles, and genetic analysis of the ZPR1, APOA5, and GCKR genes were performed. SLE patients were divided into two groups according to the presence or absence of carotid plaques. Patients with carotid plaque had higher plasma TG (1.5 vs. 0.9 mmol/L, p = 0.001), Non-HDL-C (3.5 vs. 3.1 mmol/L, p = 0.025), and apoB concentrations (1.0 vs. 0.9 g/L, p = 0.010) and a higher prevalence of hypertension (80 vs. 37.5%, p = 0.003) than patients without carotid plaque. The GCKR C-allele was present in 83.3% and 16.7% (p = 0.047) of patients with and without carotid plaque, respectively. The GCKR CC genotype (OR = 0.026; 95% CI: 0.001 to 0.473, p = 0.014), an increase of 1 mmol/L in TG concentrations (OR = 12.550; 95% CI: 1.703 to 92.475, p = 0.013) and to be hypertensive (OR = 9.691; 95% CI: 1.703 to 84.874, p = 0.040) were independently associated with carotid atherosclerosis. In summary, plasma TG concentrations, CGKR CC homozygosity, and hypertension are independent predictors of carotid atherosclerosis in women with SLE.

Programmed cell death-1 rs11568821 and interleukin-28B rs12979860 polymorphisms in autoimmune hepatitis

BackgroundAutoimmune hepatitis (AIH) is a relatively rare chronic liver disease of unknown etiology. The genetic background affects susceptibility, clinical phenotype, and prognosis. The programmed cell death-1 rs11568821 polymorphism (PD1.3) has been associated with susceptibility to autoimmune diseases. The interleukin-28B (IL28B) rs12979860 polymorphism has been associated with steatosis, inflammation, and fibrosis in liver diseases. AimOur aim was to investigate for the first time the incidence and clinical significance of PD1.3 and IL28B rs12979860 in AIH. MethodsTwo hundred patients with AIH were evaluated, while 100 healthy subjects were used as controls. Genotyping was performed with in-house allelic discrimination End-Point PCR. ResultsThe SNP PD1.3/A was present in 36/200 (18%) AIH patients compared to 28/100 (28%) healthy controls (p = 0.065). The AA/GA genotypes were not associated with the mode of presentation of AIH, the histological grade or stage, the presence of cirrhosis, risk of disease progression, response to treatment and survival. The IL28B rs12979860 genotype distribution was CC 79/200 (39.5%), TT 36/200 (18%) and CT 85/200 (42.5%), in similar rates with healthy controls (p = 0.878). Inflammatory activity and fibrosis stage did not differ between CC homozygotes and CT/TT carriers. LDL cholesterol was significantly higher in CC than CT/TT patients (P = 0.027), though no differences was found regarding the presence of steatosis or steatohepatitis. On-treatment response to immunosuppressive treatment was not affected by the IL28B rs12979860 polymorphism. However, CC homozygotes AIH patients achieved treatment withdrawal in significantly higher rates (OR 2.3, 95%CI: 1.1–4.7, P = 0.02) irrespective of the presence of steatosis or steatohepatitis. ConclusionsThe PD1.3 and IL28B rs12979860 variants are unlikely to contribute to AIH susceptibility, disease presentation and prognosis. The IL28B rs12979860 is not associated with the presence of concurrent steatosis or steatohepatitis. However, although on-treatment response rates to immunosuppression were not affected by the IL28B rs12979860 polymorphism, AIH patients with CC homozygosity were more likely to achieve complete treatment withdrawal. This novel finding needs validation and further clarification from larger multicenter studies.

Interleukin 6 gene polymorphism is associated with protein serum level and disease activity in Polish patients with rheumatoid arthritis.

Interleukin 6 (IL-6) is a pro-inflammatory cytokine involved in the development of rheumatoid arthritis (RA). The present study aimed to determine the possible association of the IL6 (rs1800795, G > C) polymorphism with RA susceptibility, disease progression and protein serum levels. Distribution of IL6 alleles and genotypes was similar in RA patients and controls. As expected, patients before induction of anti-tumour necrosis factor agents had significantly higher IL-6 levels as compared with controls (P = 0.002). The CC homozygous patients were characterised with the highest average concentrations of this pro-inflammatory cytokine before treatment (P = 0.028), and they also more frequently presented with more active disease (P = 0.048). These results imply that the IL6 rs1800795 CC homozygosity may play a rather unfavourable role in RA.

Apolipoprotein A53'-UTR variants and cardiometabolic traits in Koreans: results from the Korean genome and epidemiology study and the Korea National Health and Nutrition Examination Survey

BACKGROUND/OBJECTIVESThis study aimed to test the association between APOA5 3'-UTR variants (rs662799) and cardiometabolic traits in Koreans.SUBJECTS/METHODSFor this study, epidemiological data, Apolipoprotein A5 (APOA5) genotype information, and lymphoblastoid cell line (LCL) biospecimens from a subset of the Ansung-Ansan cohort within the Korean Genome and Epidemiology study (KoGES-ASAS; n = 7,704) as well as epidemiological data along with genomic DNA biospecimens of participants from a subset of the Korea National Health and Nutrition Examination Survey (KNHANES 2011-12; n = 2,235) were obtained. APOA5 mRNA expression was also measured.RESULTSAPOA5 rs662799 genotype distributions in both the KoGES-ASAS and KNHANES groups were 50.6% for TT, 41.3% for TC, and 8.1% for CC, which are similar to those in previous reports. In both groups, minor C allele carriers, particularly subjects with CC homozygosity, had lower high-density lipoprotein (HDL) cholesterol and higher triglyceride levels than TT homozygotes. Linear regression analysis showed that the minor C allele significantly contributed to reduction of circulating HDL cholesterol levels [β = −2.048, P < 0.001; β = −2.199, P < 0.001] as well as elevation of circulating triglyceride levels [β = 0.053, P < 0.001; β = 0.066, P < 0.001] in both the KoGES-ASAS and KNHANES groups. In addition, higher expression levels of APOA5 in LCLs of 64 healthy individuals were negatively associated with body mass index (r = −0.277, P = 0.027) and circulating triglyceride level (r = −0.340, P = 0.006) but not significantly correlated with circulating HDL cholesterol level. On the other hand, we observed no significant difference in the mRNA level of APOA5 according to APOA5 rs662799 polymorphisms.CONCLUSIONSThe C allele of APOA5 rs662799 was found to be significantly associated with cardiometabolic traits in a large Korean population from the KoGES-ASAS and KNHANES. The effect of this genotype may be associated with post-transcriptional regulation, which deserves further experimental confirmation.

Non Favorable Genotype is Predominant at IL28B RS12979860 Polymorphism in Hepatitis B Related Hepatocellular Carcinoma

Background and Aim: The highest incidence of HCC is in Asia, accounting for about 76% of all cases worldwide. In South East Asia, hepatitis B is the most common underlying cause. Although numerous associations between environmental factors (e.g. cigarette smoking, heavy alcohol drinking, male gender, older age), viral factors (e.g. viral load, active replication, genotype, core promoter mutations) and the development of HCC in chronic HBV infection have been identified, a clear understanding of the role of host genetics remains illusive. Bangladesh is a densely populated country with about 160 million populations, where HBsAg positivity in the healthy population is 5.4%. The aim is to evaluate the role of host IL28B (interleukin 28B; interferon lambda 3) single nucleotide polymorphism (SNP) in predicting hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) susceptibility. Methods: Single SNP in the IL28B gene (rs12979860C/T) were examined in 116 subjects (including 44 HBV-related HCC patients, 42 non-HCC patients with chronic hepatitis B and 30 healthy controls). The study was done at the Department of Hepatology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka from January 2012 to December 2013. The polymorphism of IL28B rs12979860 was analyzed by a genotyping technique, based on polymerase chain reaction (PCR) followed by restriction enzyme analysis at the Department of Microbiology & Immunology, BSMMU. Results: The frequency of CC homozygosity was 70% in healthy controls and 45.5% in HCC, the difference being statistically significant (χ2 = 4.35, P = 0.03). Statistically significant difference was also seen between non-HCC patients with chronic hepatitis B (CHB) (69%) and HCC (45.5%) (χ2 = 4.35, P = 0.03). However, this significant finding was not seen between non-HCC patients with chronic hepatitis B (CHB) and healthy controls. Carriers of the minor T allele in rs12979860 had a higher risk of HCC compared with non-carriers (χ2 = 4.78, P = 0.02). Conclusion: Our results suggest that, T allele and non-CC genotypes have strong predictive effect of developing HCC and IL28Brs 12979860C/T polymorphism might influence susceptibility to HCC. The author has none to declare.

Elevated plasma YKL-40, lipids and lipoproteins, and ischemic vascular disease in the general population

Background and Purpose— We tested the hypothesis that observationally and genetically elevated YKL-40 is associated with elevated lipids and lipoproteins and with increased risk of ischemic vascular disease. Methods— We conducted cohort and Mendelian randomization studies in 96 110 individuals from the Danish general population, with measured plasma levels of YKL-40 (n=21 647), plasma lipids and lipoproteins (n=94 461), and CHI3L1 rs4950928 genotype (n=94 579). Results— From 1977 to 2013, 3256 individuals developed ischemic stroke, 5629 ischemic cerebrovascular disease, 4183 myocardial infarction, and 10 271 developed ischemic heart disease. The 91% to 100% versus 0% to 33% YKL-40 percentile category was associated with a 34% increase in triglycerides, but only with minor changes in other lipids and lipoproteins. For these categories, the multifactorially adjusted hazard ratio was 1.99 (95% confidence interval, 1.49–2.67) for ischemic stroke, 1.85 (1.44–2.37) for ischemic cerebrovascular disease, 1.28 (0.95–1.73) for myocardial infarction, and 1.23 (1.01–1.51) for ischemic heart disease. When compared with rs4950928 CC homozygosity, the presence of G-allele was associated with a doubling (GC) or tripling (GG) in YKL-40 levels, but not with triglyceride levels or with risk of ischemic vascular disease. A doubling in YKL-40 was associated with a multifactorially adjusted observational hazard ratio for ischemic stroke of 1.18 (1.11–1.27), and a genetic odds ratio of 1.04 (0.95–1.15). Corresponding risk estimates were 1.15 (1.09–1.22) observationally and 1.06 (0.99–1.14) genetically for ischemic cerebrovascular disease, 1.08 (1.00–1.15) observationally and 1.04 (0.96–1.13) genetically for myocardial infarction, and 1.07 (1.02–1.12) observationally and 1.01 (0.96–1.07) genetically for ischemic heart disease. Conclusions— Elevated YKL-40 was associated with a 34% increase in triglyceride levels and with a 2-fold increased risk of ischemic stroke, whereas genetically elevated YKL-40 were not.

Association of Two Polymorphic Codons in P53 and ABCC1 Promoter with Prostate Cancer.

In prostate cancer, mutated p53 alleles typically contain missense single-base substitution in codon 72 that resides within exons 5-8. Stable p53 proteins in tumor cell nuclei have been associated with malignancy. A role of p53 is the regulation of drug transporters like ABCC1 (MRP1) by an effect on promoter region. The objective of this study was to identify association of mutations of p53 at codon 72 and 282 and promoter region of ABCC1 with increased risks of prostate cancer. Formalin fixed, paraffin-embedded malignant tissues of 45 patients and 45 control samples were evaluated. PCR-RFLP using BstUI for codon 72 and HpaII restriction enzyme for codon 282 p53 gene, and G-1666A promoter region of ABCC1 gene was performed. To assess the frequency of these mutations and to detect new mutations in cancerous samples, PCR-SSCP analysis was performed. The frequencies of CC, GC and GG genotypes of codon 72 of p53 were 33.33%, 46.67% and 20.00% in patients with cancer and 15.56%, 48.89% and 35.55% in controls, respectively. The relative allele frequencies of ABCC1 promoter polymorphism were 60.00% A and 40.00% G in patients as opposed to 37.78% for A and 62.22% for G in controls. Genotypic frequencies of p53 codon 72 and G1666A of ABCC1 in patients vs. Controls were statistically significant(p<0.05). The study of these samples with PCR-SSCP displayed some new banding patterns. The present findings suggest that CC homozygosity in codon 72 of p53 gene and AA genotype in G-1666A of ABCC1 gene may play a role in combination in prostate cancer and increased susceptibility for this malignancy in the Iranian Kurdish population.

Polymorphisms in PRKCDBP, a Transcriptional Target of TNF-α, Are Associated With Inflammatory Bowel Disease in Korean.

Background/AimsEmerging data indicate that polymorphic sequence variations in the tumor necrosis factor alpha (TNF-α) gene may affect its production, and be associated with the risk of inflammatory bowel disease (IBD). PRKCDBP is a putative tumor suppressor gene and a transcriptional target of TNF-α. The aim of this case-control study is to explore the possible association of single nucleotide polymorphisms (SNPs) in PRKCDBP with the development of IBD in Koreans.MethodsGenotyping analysis of four SNPs of PRKCDBP [rs35301211 (G210A), rs11544766 (G237C), rs12294600 (C797T), and rs1051992 (T507C)] was performed on 170 ulcerative colitis (UC),131 Crohn's disease (CD) patients, and 100 unrelated healthy controls using polymerase chain reaction and restriction fragment length polymorphism.ResultsHeterozygous configuration of three SNPs (G210A, G237C, and C797T) was very rare in both patients and healthy controls. However, allele frequencies of the T507C SNP showed a significant difference between UC patients and controls (P=0.037). The CC genotype of the T507C SNP was identified in 46.6% (61 of 131) of CD and 49.4% (84 of 170) of UC patients, but only in 33.0% (33 of 100) of healthy controls. Furthermore, CC homozygosity was more prevalent than TC heterozygosity in both CD and UC patients versus controls (P=0.016; gender-adjusted odds ratio [aOR], 2.16; 95% confidence interval [CI], 1.16-4.04 and P=0.009; aOR, 2.09; 95% CI, 1.193.64; respectively)ConclusionsOur results suggest that the T507C SNP in PRKCDBP, a TNF-α-inducible gene, might be associated with susceptibility to IBD (particularly UC) development in Koreans.

Association of innate immune IFIH1 gene polymorphisms with dilated cardiomyopathy in a Chinese population

The interferon-induced helicase C domain-containing protein 1 (IFIH1) is a cytosolic RNA sensor belonging to the pattern-recognition receptor (PPR) family. Activation of PPRs on innate immune cells is widely believed to control the development of virus-induced autoimmunity in myocarditis and subsequent dilated cardiomyopathy (DCM). We conducted a pilot study to test whether single nucleotide polymorphisms (SNPs) in IFIH1 were associated with the risk and prognosis of DCM. The TaqMan SNP Genotyping Assay was used to genotype rs1990760 and rs3747517 in 351 DCM patients and 359 controls. The frequency of T allele and CT/TT genotypes at rs1990760 were significantly increased in DCM patients compared to control subjects (p = 0.046 and p = 0.027, respectively). The CC homozygosity was associated with worse prognosis expressed by the endpoint of cardiac death compared with allele T carriers of rs3747517 in both univariable (p = 0.04) and multivariable survival analysis after adjusting for age, sex, left ventricular end-diastolic diameter and ejection fraction (p = 0.01). The results revealed that rs1990760 was associated with susceptibility to DCM and rs3747517 played a role in the prognostic assessment of DCM, reflecting the distinct genetic contributions of innate IFIH1 polymorphisms in controlling the onset and outcome of DCM.

Genomewide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202

Atazanavir-associated hyperbilirubinemia can cause premature discontinuation of atazanavir and avoidance of its initial prescription. We used genomewide genotyping and clinical data to characterize determinants of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202. Plasma atazanavir pharmacokinetics and indirect bilirubin concentrations were characterized in HIV-1-infected patients randomized to atazanavir/ritonavir-containing regimens. A subset had genomewide genotype data available. Genomewide assay data were available from 542 participants, of whom 475 also had data on estimated atazanavir clearance and relevant covariates available. Peak bilirubin concentration and relevant covariates were available for 443 participants. By multivariate analysis, higher peak on-treatment bilirubin levels were found to be associated with the UGT1A1 rs887829 T allele (P=6.4×10(-12)), higher baseline hemoglobin levels (P=4.9×10(-13)), higher baseline bilirubin levels (P=6.7×10(-12)), and slower plasma atazanavir clearance (P=8.6×10(-11)). For peak bilirubin levels greater than 3.0 mg/dl, the positive predictive value of a baseline bilirubin level of 0.5 mg/dl or higher with hemoglobin concentrations of 14 g/dl or higher was 0.51, which increased to 0.85 with rs887829 TT homozygosity. For peak bilirubin levels of 3.0 mg/dl or lower, the positive predictive value of a baseline bilirubin level less than 0.5 mg/dl with a hemoglobin concentration less than 14 g/dl was 0.91, which increased to 0.96 with rs887829 CC homozygosity. No polymorphism predicted atazanavir pharmacokinetics at genomewide significance. Atazanavir-associated hyperbilirubinemia is best predicted by considering UGT1A1 genotype, baseline bilirubin level, and baseline hemoglobin level in combination. Use of ritonavir as a pharmacokinetic enhancer may have abrogated genetic associations with atazanavir pharmacokinetics.

Endophenotypes and serotonergic polymorphisms associated with treatment response in obsessive-compulsive disorder

OBJECTIVES:Approximately 40-60% of obsessive-compulsive disorder patients are nonresponsive to serotonin reuptake inhibitors. Genetic markers associated with treatment response remain largely unknown. We aimed (1) to investigate a possible association of serotonergic polymorphisms in obsessive-compulsive disorder patients and therapeutic response to selective serotonin reuptake inhibitors and (2) to examine the relationship between these polymorphisms and endocrine response to intravenous citalopram challenge in responders and non-responders to serotonin reuptake inhibitors and in healthy volunteers.METHODS:Patients with obsessive-compulsive disorder were classified as either responders or non-responders after long-term treatment with serotonin reuptake inhibitors, and both groups were compared with a control group of healthy volunteers. The investigated genetic markers were the G861C polymorphism of the serotonin receptor 1Dβ gene and the T102C and C516T polymorphisms of the serotonin receptor subtype 2A gene.RESULTS:The T allele of the serotonin receptor subtype 2A T102C polymorphism was more frequent among obsessive-compulsive disorder patients (responders and non-responders) than in the controls (p<0.01). The CC genotype of the serotonin receptor subtype 2A C516T polymorphism was more frequent among the non-responders than in the responders (p<0.01). The CC genotype of the serotonin receptor subtype 1Dβ G681C polymorphism was associated with higher cortisol and prolactin responses to citalopram (p<0.01 and p<0.001, respectively) and with a higher platelet-rich plasma serotonin concentration among the controls (p<0.05). However, this pattern was not observed in the non-responders with the same CC genotype after chronic treatment with serotonin reuptake inhibitors. This CC homozygosity was not observed in the responders.

A SNP site in pri-miR-124 changes mature miR-124 expression but no contribution to Alzheimer's disease in a Mongolian population

Increasing evidence shows that single nucleotide polymorphisms (SNPs) or mutations in microRNAs (miRNAs) sequence may affect the processing and function of miRNAs and participate in the occurrence of diseases. Although many SNPs of miRNAs were found, their functions in the pathological process of nerve cells were only just emerging. In the present study, the effect of the SNP of one neuronal miRNA, miR-124, on miRNA biogenesis and human genetic disease was investigated using in vitro cell line model and Alzheimer's disease (AD) in the Mongolian population. Bioinformatics prediction showed that a common G/C polymorphism designated rs531564 was found in the pri-miR-124 and the G allele changed the formation of a ring-shaped structure in the predicted secondary structure of the pri-miRNA for miR-124-1. Northern blot and real-time PCR analysis showed that the amount of mature miR-124 from the C/G heterozygosity of rs531564 was increased compared with the CC or GG homozygosity of rs531564. The expression of mature miR-124 from GG homozygosity was also higher than that from CC homozygosity. But in an association study of AD patients and controls, neither genotype nor allele distribution difference was found in AD patients compared with controls. Collectively, the present study is the first to evaluate the relationship between miR-124 and AD in the Mongolian population. SNP rs531564 of miR-124 may not represent a risk factor in the development of AD among Mongolian population.

Genetic variation in IL28B is associated with the development of hepatitis B-related hepatocellular carcinoma.

To evaluate the role of host IL28B (interleukin 28B; interferon lambda 3) single nucleotide polymorphisms (SNPs) in predicting hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) susceptibility, three SNPs in the IL28B gene (rs12979860C/T, rs8099917G/T and rs12980275G/A) were examined in 330 subjects (including 154 HBV-related HCC patients, 86 non-HCC patients with chronic hepatitis B (CHB), 43 HBV self-limited infections and 47 healthy controls). Notably, the frequency of CC homozygosity was 91.5% in healthy controls and 72.9% in CHB, the difference being statistically significant (χ(2) = 6.40, P = 0.01). The statistically difference was seen between healthy controls (91.5%) and HCC (74.7%) (χ(2) = 6.05, P = 0.01). However, this significant finding was not seen between HBV self-limited and healthy controls. Carriers of the minor T allele in rs12979860 had a higher risk of HCC compared with non-carriers (χ(2) = 4.44, P = 0.04). Haplotype analyses revealed significant association between haplotype C-T-A and healthy controls, but not with the HCC group (96.6 vs. 82.0%, χ(2) = 6.08, P = 0.01). Analyses of genotype combination and gene-gene interaction showed that there was a positive interaction between rs12979860 and rs12980275, with an OR rate of 11.79 (likelihood test, P = 0.04). Our results suggest that the IL28B rs12979860 C/T polymorphism might affect susceptibility to the chronic HBV infection and progression of HCC. Of note, the T allele and non-CC genotypes have strong predictive effect of increasing susceptibility of chronic HBV infection and HCC.

Single nucleotide polymorphisms in miRNA binding sites and miRNA genes as breast/ovarian cancer risk modifiers in Jewish high‐risk women

We hypothesized that aberrant gene silencing by miRNA may affect mutant BRCA penetrance. To test this notion, frequency of single nucleotide polymorphisms (SNPs; n = 42) within predicted miRNA binding sites or miRNA precursors were determined and compared in 363 BRCA1 mutation carriers: asymptomatic (n = 160), breast cancer (n = 140) and ovarian cancer (n = 63) patients, and in 125 BRCA2 mutation carriers: asymptomatic (n = 48), breast cancer (n = 58) and ovarian cancer (n = 19) patients. Overall, 16 of 42 SNPs were polymorphic, 11 had a minor allele frequency greater than 5% and 9 of them maintained the Hardy-Weinberg Equilibrium. Based on Cox regression and Kaplan-Meier analyses, statistically significant differences were noted in BRCA2 mutation carriers by health status in 3 SNPs: CC homozygosity at rs6505162 increased ovarian cancer risk (RR 2.77; p = 0.028; 95% CI, 1.11-6.9); heterozygote SNP carriers of rs11169571 had an approximately 2 fold increased risk for developing breast/ovarian cancer, whereas heterozygotes of the rs895819 SNP had an approximately 50% reduced risk for developing breast/ovarian cancer. This study provides preliminary evidence for another regulatory level of penetrance of deleterious mutations in cancer predisposition genes.

Missense single nucleotide polymorphism of the ADAM12 gene is associated with radiographic knee osteoarthritis in middle-aged Estonian cohort

One of the recognized candidate genes of osteoarthritis (OA) is the ADAM metallopeptidase domain 12 (meltrin alpha) gene. We investigated the potential role of two single nucleotide polymorphisms (SNP) of the ADAM12 gene in susceptibility to radiographic knee OA and its progression in an Estonian cohort. The rs3740199 and rs1871054 polymorphisms were genotyped according to restriction fragment polymorphism in a population-based cohort consisting of 189 subjects selected from the age group 32-55 years. The radiological features of OA were measured in the tibio- and patellofemoral joints (PFJ). The X-ray investigation was repeated 3 years later for estimation of OA progression. We found statistically significant association between rs3740199 polymorphism and patellofemoral OA in male patients (P=0.014), genetic risk was mostly related to CC homozygosity. The same SNP also affected the presence of advanced grade (II+III) osteophytes in the whole group (P=0.042) and the occurrence of osteophytes on the patellar margins in the PFJ (P=0.046). In OA progression the most significant association was found between joint space narrowing of the tibiofemoral joint and rs3740199 SNP in women (P=0.018). The rs1871054 polymorphism was not related to OA susceptibility or to progression traits. In our study the haplotype GC (rs3740199/rs1871054) was associated with reduced risk for development of osteophytes in the PFJ (P=0.041). We conclude that rs3740199 polymorphism may affect occurrence of knee OA and its progression. We also hypothesize that the genetic contribution of ADAM12 to OA is remarkably gender-dependent and anatomical site-specific.